Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects.
Caroline V. L. Moreira, Ana Luiza G Faria, Daiany P B Silva, Paulo César Ghedini, José Luis Rodrigues Martins, Adam W Keasling, Jordan K Zjawiony, Pankaj Pandey, Robert J Doerksen, Hamilton B Napolitano, Fábio F Da Rocha, Elson A Costa, James O Fajemiroye
Fitoterapia June 1, 2023 DOI: 10.1016/j.fitote.2023.105488 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | P-3l |
| Dose | 1, 3, 10, and 30 mg/kg |
| Topics | Salvia divinorum |
| Keywords | Antinociceptive Anxiolytic Benzodiazepine site Opioid receptors P-3 l Drug development: p-3l Salvinorin analogue New compound Promising candidate Therapeutic development Compound pharmacology: docking Computational docking Mechanism of action Pain relief Anxiety relief Pain responses Anxiety-like behaviors Beneficial actions |
| Citations | 2 |
| Key points | The salvinorin A analogue P-3l reduces pain and anxiety-like behaviors in mice through opioid receptor and benzodiazepine site mechanisms without apparent toxicity. |
Abstract
Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of salvinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective opioid receptor antagonist), naloxonazine (antagonist of specific subtypes mu1 of μ-OR), and nor-binaltorphimine (selective ĸ-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the opioid receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for additional pharmacological characterization.
Comparable studies
Other preclinical and animal studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Mice | 2005 | Experimental study | |
| Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents Male Sprague-Dawley rats and male Albino Swiss mice | 2009 | Experimental study | |
| Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Wistar rats | 2008 | Experimental study | |
| Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Rats | 2010 | Experimental study | |
| The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Rhesus monkeys | 2004 | Experimental study | n = 3 |
Citations in the library
Cites 13
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae) Journal of the Chemical Society Perkin Transactions 1 1982
- Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug and Alcohol Dependence May 1, 2011
- Antidepressant Effects of the Herb Salvia Divinorum: A Case Report Journal of Clinical Psychopharmacology December 1, 2001
- A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3]-salvinorin A. Bioorganic & Medicinal Chemistry Letters October 18, 2004
and 8 more in the library